title: Inhibition of C2C12 myotube atrophy by a novel HSP70 inducer, celastrol, via activation of Akt1 and ERK1/2 pathways.
abstract: Celastrol (CEL) is known as a potent inducer of heat shock protein (HSP) in non-muscle cells and exhibits cytoprotective function and inhibitory effects on proteasome and glucocorticoid receptor activities. To investigate an anti-atrophic effect of CEL on skeletal muscle cells, C2C12 myotubes were treated with 150 μM dexamethasone (DEX) for 24h and 1.5 μM CEL was added for the last 6h during the 24h DEX treatment. Compared to the control, the myotube diameter was reduced by a factor of 0.30 by DEX, but CEL treatment almost abrogated the DEX-induced atrophy. CEL treatment also increased expression of HSP72 and phosphorylation of heat shock transcription factor 1 (p-HSF1) 11-fold and 3.4-fold, respectively, as well as accumulation of p-HSF1 in the nucleus. Furthermore, CEL treatment elevated activities of Akt1, p70/S6K and ERK1/2 2.0- to 4.4-fold whereas DEX had no effect on these signaling activities. Inhibition of Akt1 and ERK1/2 pathways by specific inhibitors confirmed CEL-induced anti-atrophic effect. Moreover, DEX-mediated downregulation of FoxO3 phosphorylation and upregulation of MuRF1 expression and proteasome activity were abrogated by CEL treatment. These results demonstrate a novel anti-atrophic function of CEL in muscle cells via both activation of protein anabolic signals and suppression of catabolic signaling activities.
authors.affiliation: Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju, Gangwon-Do, Republic of Korea.
authors.forename: Taesik
authors.initials: T
authors.lastname: Gwag
authors.forename: Kyoungsook
authors.initials: K
authors.lastname: Park
authors.forename: Eunjung
authors.initials: E
authors.lastname: Kim
authors.forename: Chaeyeon
authors.initials: C
authors.lastname: Son
authors.forename: Junsoo
authors.initials: J
authors.lastname: Park
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nikawa
authors.forename: Inho
authors.initials: I
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D053978:Pentacyclic Triterpenes; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D014315:Triterpenes; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C050414:celastrol
keywords: Celastrol; Countermeasure; Dexamethasone; HSF1; HSP72; Muscle atrophy